Rizza R A, Cryer P E, Gerich J E
J Clin Invest. 1979 Jul;64(1):62-71. doi: 10.1172/JCI109464.
To further characterize mechanisms of glucose counterregulation in man, the effects of pharmacologically inducd deficiencies of glucagon, growth hormone, and catecholamines (alone and in combination) on recovery of plasma glucose from insulin-induced hypoglycemia and attendant changes in isotopically ([3-(3)H]glucose) determined glucose fluxes were studied in 13 normal subjects. In control studies, recovery of plasma glucose from hypoglycemia was primarily due to a compensatory increase in glucose production; the temporal relationship of glucagon, epinephrine, cortisol, and growth hormone responses with the compensatory increase in glucose appearance was compatible with potential participation of all these hormones in acute glucose counterregulation. Infusion of somatostatin (combined deficiency of glucagon and growth hormone) accentuated insulin-induced hypoglycemia (plasma glucose nadir: 36+/-2 ng/dl during infusion of somatostatin vs. 47+/-2 mg/dl in control studies, P < 0.01) and impaired restoration of normoglycemia (plasma glucose at min 90: 73+/-3 mg/dl at end of somatostatin infusion vs. 92+/-3 mg/dl in control studies, P<0.01). This impaired recovery of plasma glucose was due to blunting of the compensatory increase in glucose appearance since glucose disappearance was not augmented, and was attributable to suppression of glucagon secretion rather than growth hormone secretion since these effects of somatostatin were not observed during simultaneous infusion of somatostatin and glucagon whereas infusion of growth hormone along with somatostatin did not prevent the effect of somatostatin. The attenuated recovery of plasma glucose from hypoglycemia observed during somatostatin-induced glucagon deficiency was associated with plasma epinephrine levels twice those observed in control studies. Infusion of phentolamine plus propranolol (combined alpha-and beta-adrenergic blockade) had no effect on plasma glucose or glucose fluxes after insulin administration. However, infusion of somatostatin along with both phentolamine and propranolol further impaired recovery of plasma glucose from hypoglycemia compared to that observed with somatostatin alone (plasma glucose at end of infusions: 52+/-6 mg/dl for somatostatin-phentolamine-propranolol vs. 72+/-5 mg/dl for somatostatin alone, P < 0.01); this was due to further suppression of the compensatory increase in glucose appearance (maximal values: 1.93+/-0.41 mg/kg per min for somatostatin-phentolamine-propranolol vs. 2.86+/-0.32 mg/kg per min for somatostatin alone, P < 0.05). These results indicate that in man (a) restoration of normoglycemia after insulin-induced hypoglycemia is primarily due to a compensatory increase in glucose production; (b) intact glucagon secretion, but not growth hormone secretion, is necessary for normal glucose counterregulation, and (c) adrenergic mechanisms do not normally play an essential role in this process but become critical to recovery from hypoglycemia when glucagon secretion is impaired.
为进一步阐明人体葡萄糖反向调节机制，我们研究了13名正常受试者中，通过药理学方法诱导胰高血糖素、生长激素和儿茶酚胺缺乏（单独及联合缺乏）对胰岛素诱导的低血糖后血浆葡萄糖恢复以及同位素标记（[3-(3)H]葡萄糖）测定的葡萄糖通量伴随变化的影响。在对照研究中，低血糖后血浆葡萄糖的恢复主要归因于葡萄糖生成的代偿性增加；胰高血糖素、肾上腺素、皮质醇和生长激素反应与葡萄糖出现的代偿性增加之间的时间关系表明，所有这些激素都可能参与急性葡萄糖反向调节。输注生长抑素（胰高血糖素和生长激素联合缺乏）会加重胰岛素诱导的低血糖（输注生长抑素期间血浆葡萄糖最低点：36±2 ng/dl，而对照研究中为47±2 mg/dl，P<0.01），并损害血糖恢复正常（90分钟时血浆葡萄糖：生长抑素输注结束时为73±3 mg/dl，对照研究中为92±3 mg/dl，P<0.01）。血浆葡萄糖恢复受损是由于葡萄糖出现的代偿性增加受到抑制，因为葡萄糖消失并未增加，这归因于胰高血糖素分泌受抑制而非生长激素分泌受抑制，因为在同时输注生长抑素和胰高血糖素期间未观察到生长抑素的这些作用，而与生长抑素一起输注生长激素并不能防止生长抑素的作用。生长抑素诱导的胰高血糖素缺乏期间观察到的低血糖后血浆葡萄糖恢复减弱与血浆肾上腺素水平是对照研究中观察值的两倍有关。输注酚妥拉明加普萘洛尔（α和β肾上腺素能联合阻断）对胰岛素给药后的血浆葡萄糖或葡萄糖通量无影响。然而，与单独输注生长抑素相比，同时输注生长抑素、酚妥拉明和普萘洛尔会进一步损害低血糖后血浆葡萄糖的恢复（输注结束时血浆葡萄糖：生长抑素-酚妥拉明-普萘洛尔组为52±6 mg/dl，生长抑素单独输注组为72±5 mg/dl，P<0.01）；这是由于葡萄糖出现的代偿性增加进一步受到抑制（最大值：生长抑素-酚妥拉明-普萘洛尔组为1.93±0.41 mg/kg每分钟，生长抑素单独输注组为2.86±0.32 mg/kg每分钟，P<0.05）。这些结果表明，在人体中：（a）胰岛素诱导的低血糖后血糖恢复正常主要归因于葡萄糖生成的代偿性增加；（b）完整的胰高血糖素分泌而非生长激素分泌是正常葡萄糖反向调节所必需的；（c）肾上腺素能机制通常在这一过程中不发挥重要作用，但当胰高血糖素分泌受损时，对低血糖恢复至关重要。
